alirocumab in patients with recent acute coronary syndrome ... · acc.18 3 •remains high despite...

The ODYSSEY OUTCOMES Trial: Topline Results

Alirocumab in Patients After Acute Coronary Syndrome

Gregory G. Schwartz, Michael Szarek, Deepak L. Bhatt, Vera Bittner, Rafael Diaz, Jay Edelberg,

Shaun G. Goodman, Corinne Hanotin, Robert Harrington, J. Wouter Jukema,

Guillaume Lecorps, Angèle Moryusef, Robert Pordy, Matthew Roe, Harvey D. White, Andreas Zeiher,

Ph. Gabriel Steg

On behalf of the ODYSSEY OUTCOMES Investigators and Committees

American College of Cardiology – 67th Scientific SessionsMarch 10, 2018

ClinicalTrials.gov: NCT01663402

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Disclosures

• The trial was funded by Sanofi and Regeneron Pharmaceuticals

• Ph. Gabriel Steg discloses the following relationships:

- Research grants from Bayer, Merck, Sanofi, and Servier

- Speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen,

Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck, Novartis, Novo-

Nordisk, Pfizer, Regeneron Pharmaceuticals, Sanofi, and Servier

• Gregory G. Schwartz discloses research support to his institution

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• Remains high despite evidence-based preventive therapies

• Is related, in part, to levels of low-density lipoprotein cholesterol (LDL-C)

• Is reduced when LDL-C is lowered by

• Statin therapy, compared with placebo1

• High-intensity, compared with moderate-intensity statin therapy2

• Ezetimibe, compared with placebo, added to statin3

Residual Risk After Acute Coronary Syndrome

1. Schwartz GG, et al. JAMA 2001;285:1711-8. 2. Cannon CP, et al. NEJM 2004;350:1495-504. 3. Cannon CP, et al. NEJM 2015;372:2387-97.

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Alirocumab

• PCSK9 is a validated target for risk reduction in stable atherosclerotic cardiovascular disease1–3

• A fully human monoclonal antibody against PCSK9

• Produces substantial and sustained reductions in LDL-C and other atherogenic lipoproteins2

• Has been safe and well-tolerated in studies to date4

PCSK9, proprotein convertase subtilisin/kexin type 91. Sabatine et al, NEJM 2017;376:713-22. 2. Robinson JG et al. NEJM 2015;372:1489-99.3. Ridker PM et al. NEJM 2017;376:1527-39. 4. Robinson JG et al. JACC 2017;69:471-82.

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Study Hypothesis

Alirocumab, versus placebo, reduces cardiovascular (CV)

morbidity and mortality after recent acute coronary

syndrome (ACS) in patients with elevated levels of

atherogenic lipoproteins despite intensive or maximum-

tolerated statin therapy

Schwartz GG, et al. Am Heart J 2014;168:682-689.e1.

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Main Inclusion Criteria

• Age ≥40 years

• ACS• 1 to 12 months prior to randomization

• Acute myocardial infarction (MI) or unstable angina

• High-intensity statin therapy*• Atorvastatin 40 to 80 mg daily or

• Rosuvastatin 20 to 40 mg daily or

• Maximum tolerated dose of one of these agents for ≥2 weeks

• Inadequate control of lipids• LDL-C ≥70 mg/dL (1.8 mmol/L) or

• Non-HDL-C ≥100 mg/dL (2.6 mmol/L) or

• Apolipoprotein B ≥80 mg/dL

*Patients not on statins were authorized to participate if tolerability issues were present and documentedSchwartz GG, et al. Am Heart J 2014;168:682-689.e1.

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Key Exclusion Criteria

• Uncontrolled hypertension

• NYHA class III or IV heart failure;

LVEF <25% if measured

• History of hemorrhagic stroke

• Fasting triglycerides >400 mg/dL

(4.52 mmol/L)

• Use of fibrates other than fenofibrate or fenofibric acid

• Recurrent ACS within 2 weeks prior to randomization visit

• Coronary revascularization performed within 2 weeks prior to randomization visit, or planned after randomization

• Liver transaminases >3 ULN;

hepatitis B or C infection

• Creatine kinase >3 ULN

• eGFR <30 mL/min/1.73 m2

• Positive pregnancy test

eGFR, estimated glomerular filtration rate; ULN, upper limit of normalSchwartz GG, et al. Am Heart J 2014;168:682-689.e1.

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Time of first occurrence of:

• Coronary heart disease (CHD) death, or

• Non-fatal MI, or

• Fatal or non-fatal ischemic stroke, or

• Unstable angina requiring hospitalization*

Primary Efficacy Outcome

All outcomes adjudicated by the Clinical Events Committee, under the auspices of the Duke Clinical Research Institute (DCRI). Members were unaware of treatment assignment and lipid levels

*Required all of the following:1. Hospital admission >23 h for MI symptoms, tempo in prior 48 hours and/or ≥20 min of chest discomfort at rest2. New ECG findings consistent with ischemia or infarction3. Angiographically significant obstructive coronary disease


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Major Secondary Efficacy Endpoints

Tested in the following hierarchical sequence:

• CHD event: CHD death, non-fatal MI, unstable angina requiring hospitalization, or

ischemia-driven coronary revascularization*

• Major CHD event: CHD death or non-fatal MI

• CV event: CV death, non-fatal CHD event, or non-fatal ischemic stroke

• All-cause death, non-fatal MI, non-fatal ischemic stroke

• CHD death

• CV death

• All-cause death

*Revascularization performed because of recurrent ACS, new or progressive symptoms of myocardial ischemia or new or progressive abnormalities on functional testing, except revascularization due to restenosis at a prior coronary intervention site.

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Other Secondary and Safety Endpoints

Other secondary endpoints• Components of the primary endpoint considered individually:

• CHD death

• Non-fatal MI

• Fatal and non-fatal ischemic stroke

• Unstable angina requiring hospitalization

• Ischemia-driven coronary revascularization

• Congestive heart failure requiring hospitalization

Safety endpoints• Adverse events

• Laboratory assessments

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Treatment Assignment

Post-ACS patients (1 to 12 months)

Run-in period of 2−16 weeks on high-intensity or maximum-tolerated dose of atorvastatin or rosuvastatin

At least one lipid entry criterion met

Placebo SC Q2W Alirocumab SC Q2W

Randomization


Patient and investigators remained blinded to treatment and lipid levels for the entire duration of the study

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LDL-C (mg/dL)

705025150

A Target Range for LDL-C


Undesirably highbaseline range

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LDL-C (mg/dL)

Target range

705025150



Alirocumab

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LDL-C (mg/dL)

Target range

Alirocumab

705025150



Acc

ep

tab

le r

ange

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LDL-C (mg/dL)

Target range

Alirocumab

Be

low

tar

get

705025150

Acc

ep

tab

le r

ange



We attempted to maximize the number of patients in the target range and minimize the number below target by blindly titrating alirocumab (75 or 150 mg SC Q2W) or blindly switching to placebo.

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Statistical Considerations

• All analyses conducted by independent academic statistical team at State University of New York

(SUNY) Downstate School of Public Health, in parallel with the sponsor

• Efficacy analysis by intention-to-treat (ITT)

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Statistical Considerations

• All analyses conducted by independent academic statistical team at State University of New York

(SUNY) Downstate School of Public Health, in parallel with the sponsor

• Efficacy analysis by intention-to-treat (ITT)

• Assumptions

• Cumulative incidence of primary endpoint in placebo group 11.4% at 48 months

• Baseline LDL-C 90 mg/dL; reduction to 45 mg/dL with alirocumab

• 15% expected hazard reduction for primary endpoint

• Loss to follow-up at 24 months: 1%

• Log-rank test with 1-sided 2.5% significance level

• Continuation of the trial until 1613 patients with a primary endpoint (for 90% power) AND

all surviving patients followed for ≥2 years (for adequate safety assessments), whichever

came later*

* Except for patients enrolled in China (enrollment started on May 5, 2016)

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ODYSSEY OUTCOMES: 18,924 patients randomized at 1315 sites in 57 countries, Nov 2, 2012 − Nov 11, 2017

Canada/USACanada 361US 2511

Latin AmericaArgentina 592Brazil 928Chile 132Colombia 354Guatemala 25Mexico 349Peru 208

AsiaChina 614Hong Kong 17India 521Japan 204Korea 94Malaysia 110Philippines 116Singapore 49Sri Lanka 314Taiwan 93Thailand 161

Rest of WorldAustralia 216Israel 582New Zealand 257South Africa 505

Western EuropeAustria 58Belgium 197Denmark 352Finland 116France 185 Germany 509Greece 70Italy 275Netherlands 686Norway 97Portugal 174Spain 826Sweden 250Switzerland 88UK 292

Central/Eastern EuropeBosnia–Herzegovina 156 Macedonia 132Bulgaria 333 Poland 926Croatia 70 Romania 145Czech Republic 381 Russian Federation 1109Estonia 216 Serbia 255Georgia 131 Slovakia 340Hungary 224 Slovenia 36Latvia 80 Turkey 78Lithuania 188 Ukraine 639

We thank the patients, their families, all investigators and coordinators involved in this study, and DCRI

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Argentina R. Diaz

Australia P.E. Aylward

Austria H. Drexel

Belgium P. Sinnaeve

Bosnia and Herzegovina M. Dilic

Brazil R.D. Lopes

Bulgaria N.N. Gotcheva

Canada S.G. Goodman

Chile J.-C. Prieto

China H. Yong

Colombia P. López-Jaramillo

Croatia I. Pećin

Czech Republic P. Ostadal

Denmark S. Hvitfeldt Poulsen

Estonia M. Viigimaa

Finland M.S. Nieminen

France N. Danchin

Georgia V. Chumburidze

Germany N. Marx

Greece E. Liberopoulos

Guatemala P.C. Montenegro

Valdovinos

Hong Kong H.-F. Tse

Hungary R. Gabor Kiss

India D. Xavier

Israel D. Zahger

Italy M. Valgimigli

Japan T. Kimura

Korea H. Soo Kim

Latvia A. Erglis

Lithuania A. Laucevicius

Macedonia S. Kedev

Malaysia K. Yusoff

Mexico G.A. Ramos López

Netherlands M. Alings

New Zealand H.D. White

Norway S. Halvorsen

Peru R.M. Correa Flores

Philippines R.G. Sy

Poland A. Budaj

Portugal J. Morais

Romania M. Dorobantu

Russian Federation Y. Karpov

Serbia A.D. Ristic

Singapore T. Chua

Slovakia J. Murin

Slovenia Z. Fras

Republic of South Africa A.J.

Dalby

Spain J. Tuñón

Sri Lanka H. Asita de Silva

Sweden E. Hagström

Switzerland C. Müller

Taiwan C.-E. Chiang

Thailand P. Sritara

Turkey S. Guneri

Ukraine A. Parkhomenko

UK K.K. Ray

USA P. Moriarty, M Roe, R. Vogel

ODYSSEY OUTCOMES National Leaders

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Executive Steering Committee

G.G. Schwartz and Ph.G. Steg (Co-Chairs)

D.L. Bhatt, V. Bittner, R. Diaz, S.G. Goodman, R.A. Harrington, J.W. Jukema, M. Szarek, H. White, A. Zeiher

Non-voting members: Ex officio: P. Tricoci, M.T. Roe, K.W. MahaffeySponsor representatives: C. Hanotin, G. Lecorps, A. Moryusef, R. Pordy, W.J. Sasiela, J.-F. Tamby

Clinical Events Committee P. Tricoci (Chair), J.H. Alexander, L. Armaganijan, A. Bagai, M.C. Bahit, J.M. Brennan, S. Clifton, A.D. DeVore, S. Deloatch, S. Dickey, K. Dombrowski, G. Ducrocq, Z. Eapen, P. Endsley, A. Eppinger, R.W. Harrison, C.N. Hess, M.A. Hlatky, J.D. Jordan, J.W. Knowles, B.J. Kolls, D.F. Kong, S. Leonardi, L. Lillis, R.D. Lopes, D.J. Maron, K.W. Mahaffey, J. Marcus, R. Mathews, R.H. Mehta, R.J. Mentz, H.G. Moreira, C.B. Patel, S.B. Pereira, L. Perkins, T.J. Povsic, E. Puymirat, M.T. Roe, W. Schuyler Jones, B.R. Shah, M.W. Sherwood, K. Stringfellow, D. Sujjavanich, M. Toma, C. Trotter, S.F.P. van Diepen, M.D. Wilson, A. T.-K. Yan

Data Safety Monitoring Board B. Chaitman (Chair), S.F. Kelsey, A.G. Olsson, J.-L. Rouleau, M.L. Simoons

Monitoring of safety in patients with low LDL-C values K. Alexander, C. Meloni, R.S. Rosenson, E.J.G. Sijbrands

ODYSSEY OUTCOMES Committees

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ODYSSEY OUTCOMES Trial Organization

Academic and Contract Research Organizations

Brazilian Clinical Research Institute, São Paulo, Brazil R. Lopes, F. Egydio, A. Kawakami, J. Oliveira

Canadian VIGOUR Centre, University of Alberta, Toronto, Canada S.G. Goodman, J. Wozniak

Covance, Marlow, Buckinghamshire, UK A. Matthews, C. Ratky, J. Valiris

Duke Clinical Research Institute, Durham, NC, USA L. Berdan, K. Quintero, T. Rorick

Estudios Clínicos Latino America, Rosario, Santa Fe, Argentina R. Diaz, A. Pascual, C. Rovito

French Alliance for Cardiovascular Trials, Paris, France N. Danchin, M. Bezault, E. Drouet, T. Simon

Green Lane Coordinating Centre, Kingsland, Auckland, New Zealand H.D. White, C. Alsweiler

Leuven Klinisch Coördinatiecentrum, Leuven, Belgium P. Sinnaeve, A. Luyten

South Australian Health & Medical Research Institute P. Aylward, J. Butters, L. Griffith, M. Shaw

Uppsala Kliniska Forskningscentrum, Uppsala, Sweden E. Hagstrom, L. Grunberg

Independent Statistical Team

SUNY Downstate School of Public Health M. Szarek, S. Islam

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Patient Disposition

Randomized 18,924 patients

*Ascertainment was complete for 99.1% and 99.8% of potential patient-years of follow-up for the primary endpoint and all-cause death, respectively

1955 patients experienced a primary endpoint726 patients died

Follow-up*: median 2.8 (Q1–Q3 2.3–3.4) years8242 (44%) patients with potential follow-up ≥3 years

Alirocumab(N=9462)

Placebo (N=9462)

1343 (14.2%) 1496 (15.8%) • Premature treatment discontinuation

• Blinded switch to placebo (2 consecutive LDL-C values <15 mg/dL)

• Patients lost to follow-up (vital status)

730 (7.7%) Not applicable

14 9

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Baseline Demographics

CharacteristicAlirocumab

(N=9462)Placebo

(N=9462)

Age, years, median (Q1−Q3) 58 (52−65) 58 (52−65)

Female, n (%) 2390 (25.3) 2372 (25.1)

Medical history, n (%)

Hypertension 6205 (65.6) 6044 (63.9)

Diabetes mellitus 2693 (28.5) 2751 (29.1)

Current tobacco smoker 2282 (24.1) 2278 (24.1)

Prior MI 1790 (18.9) 1843 (19.5)

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CharacteristicAlirocumab

(N=9462)Placebo

(N=9462)

Time from index ACS to randomization, months, median (Q1−Q3)

2.6 (1.7−4.4) 2.6 (1.7−4.3)

ACS type, n (%)

NSTEMI 4574 (48.4) 4601 (48.7)

STEMI 3301 (35.0) 3235 (34.2)

Unstable angina 1568 (16.6) 1614 (17.1)

Revascularization for index ACS, n (%) 6798 (71.8) 6878 (72.7)

Baseline Index Events

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Baseline Lipid Characteristics

Characteristic, mg/dL, median (Q1–Q3)Alirocumab

(N=9462)Placebo

(N=9462)

LDL-C 87 (73–104) 87 (73–104)

Non-HDL-C 115 (99−136) 115 (99−137)

Apolipoprotein B 79 (69−93) 80 (69−93)

HDL-C 43 (37−50) 42 (36−50)

Triglycerides 129 (94−181) 129 (95−183)

Lipoprotein(a) 21 (7−59) 22 (7−60)

92.5% of patients qualified on the basis of LDL-C ≥70 mg/dL

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Therapy, n (%)Alirocumab

(N=9462)Placebo

(N=9462)

High-dose atorvastatin/rosuvastatin 8380 (88.6) 8431 (89.1)

Low-/moderate-dose atorvastatin/rosuvastatin 830 (8.8) 777 (8.2)

Other statin 19 (0.2) 27 (0.3)

Ezetimibe, with or without statin 269 (2.8) 285 (3.0)

No lipid-lowering therapy* 87 (0.9) 91 (1.0)

Baseline Lipid-Lowering Therapy

*Patients not on statins were authorized to participate if tolerability issues were present and documented

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Guideline-Recommended Post-ACS Medications

Medication, n (%)Alirocumab

(N=9462)Placebo

(N=9462)

Aspirin 9050 (95.6) 9036 (95.5)

P2Y12 antagonist 8296 (87.7) 8245 (87.1)

ACE-I/ARB 7356 (77.7) 7360 (77.8)

Beta-blocker 7998 (84.5) 7992 (84.5)

ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker

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103.1

39.848.0

66.4

93.3 96.4

101.4

37.642.3

53.3

0

15

30

45

60

75

90

105

0 4 8 12 16 20 24 28 32 36 40 44 48

Me

an

LD

L-C

(m

g/d

L)

Months Since Randomization

LDL-C: ITT and On-Treatment Analyses

PlaceboITTOn-treatment*

AlirocumabITT†

On-treatment*

*Excludes LDL-C values after premature treatment discontinuation or blinded switch to placebo†All LDL-C values, including those after premature treatment discontinuation, blinded down titration, or blinded switch to placebo

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93.396.4

101.4

37.642.3

53.3

0

15

30

45

60

75

90

105

0 4 8 12 16 20 24 28 32 36 40 44 48

Me

an

LD

L-C

(m

g/d

L)

Months Since Randomization

D 55.7 mg/dL

–62.7%

D 54.1 mg/dL

–61.0%

D 48.1 mg/dL

–54.7%

LDL-C: On-Treatment Analysis

Placebo

Alirocumab

Excludes LDL-C values after premature treatment discontinuation or blinded switch to placeboApproximately 75% of months of active treatment were at the 75 mg dose

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Primary Efficacy Endpoint: MACE

MACE: CHD death,

non-fatal MI,

ischemic stroke, or

unstable angina requiring

hospitalization

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Primary Efficacy Endpoint: MACE

ARR* 1.6%

*Based on cumulative incidence

MACE: CHD death,

non-fatal MI,

ischemic stroke, or

unstable angina requiring

hospitalization

HR 0.85(95% CI 0.78, 0.93)

P=0.0003

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Primary Efficacy and Components

Endpoint, n (%)Alirocumab

(N=9462)Placebo

(N=9462)HR (95% CI)

Log-rank P-value

MACE 903 (9.5) 1052 (11.1) 0.85 (0.78, 0.93) 0.0003

CHD death 205 (2.2) 222 (2.3) 0.92 (0.76, 1.11) 0.38

Non-fatal MI 626 (6.6) 722 (7.6) 0.86 (0.77, 0.96) 0.006

Ischemic stroke 111 (1.2) 152 (1.6) 0.73 (0.57, 0.93) 0.01

Unstable angina 37 (0.4) 60 (0.6) 0.61 (0.41, 0.92) 0.02

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Main Secondary Efficacy Endpoints: Hierarchical Testing


(N=9462)Placebo

(N=9462)HR (95% CI)

Log-rank P-value

CHD event 1199 (12.7) 1349 (14.3) 0.88 (0.81, 0.95) 0.001

Major CHD event 793 (8.4) 899 (9.5) 0.88 (0.80, 0.96) 0.006

CV event 1301 (13.7) 1474 (15.6) 0.87 (0.81, 0.94) 0.0003

Death, MI, ischemic stroke

973 (10.3) 1126 (11.9) 0.86 (0.79, 0.93) 0.0003

CHD death 205 (2.2) 222 (2.3) 0.92 (0.76, 1.11) 0.38

CV death 240 (2.5) 271 (2.9) 0.88 (0.74, 1.05) 0.15

All-cause death 334 (3.5) 392 (4.1) 0.85 (0.73, 0.98) 0.026*

*Nominal P-value

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All-Cause Death

ARR† 0.6%

*Nominal P-value†Based on cumulative incidence

HR 0.85(95% CI 0.73, 0.98)

P=0.026*

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Other Efficacy Endpoints

Endpoint n (%)Alirocumab

(N=9462)Placebo

(N=9462)HR (95% CI)

Log-rank P-value

Ischemia-driven coronary revascularization

731 (7.7) 828 (8.8) 0.88 (0.79, 0.97) 0.009

Hospitalization for CHF

176 (1.9) 179 (1.9) 0.98 (0.79, 1.20) 0.84

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Primary Efficacy in Main Prespecified Subgroups

*P-values for interaction

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Primary Efficacy in Main Prespecified SubgroupsIncidence (%)

Subgroup Patients Alirocumab Placebo HR (95% CI) p-value*


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Years Since Randomization

MA

CE

(%

)

0 1 2 3 4

0

4

8

12

16

20

Number at Risk

Placebo

Alirocumab

3583 3347 3122 1290 256

3581 3365 3183 1327 233

Placebo

Alirocumab


MA

CE

(%

)

0 1 2 3 4

0

4

8

12

16

20

Number at Risk

Placebo

Alirocumab

3062 2889 2708 1195 195

3066 2880 2732 1194 213


MA

CE

(%

)

0 1 2 3 4

0

4

8

12

16

20

Number at Risk

Placebo

Alirocumab

2815 2568 2371 986 178

2814 2602 2431 1053 207

<80 mg/dL 80 to <100 mg/dL 100 mg/dL

Primary Efficacy in Main Prespecified SubgroupsIncidence (%)

Subgroup Patients Alirocumab Placebo HR (95% CI) p-value*


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Incidence (%)Subgroup Patients Alirocumab Placebo HR (95% CI) p-value*

Primary Efficacy in Main Prespecified Subgroups



MA

CE

(%

)

0 1 2 3 4

0

4

8

12

16

20

Number at Risk

Placebo

Alirocumab

3583 3347 3122 1290 256

3581 3365 3183 1327 233

Placebo

Alirocumab


MA

CE

(%

)

0 1 2 3 4

0

4

8

12

16

20

Number at Risk

Placebo

Alirocumab

3062 2889 2708 1195 195

3066 2880 2732 1194 213


MA

CE

(%

)

0 1 2 3 4

0

4

8

12

16

20

Number at Risk

Placebo

Alirocumab

2815 2568 2371 986 178

2814 2602 2431 1053 207

<80 mg/dL 80 to <100 mg/dL 100 mg/dL

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Post Hoc Analysis: All-Cause Death by Baseline LDL-C Subgroups

≥100 mg/dLHR=0.71

<80 mg/dLHR 0.89

(95% CI 0.69, 1.14)

80 to <100 mg/dLHR 1.03

(95% CI 0.78, 1.36)

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Post Hoc Analysis: All-Cause Death by Baseline LDL-C Subgroups

Pinteraction=0.12

≥100 mg/dLHR 0.71

(95% CI 0.56, 0.90)

<80 mg/dLHR 0.89

(95% CI 0.69, 1.14)

80 to <100 mg/dLHR 1.03

(95% CI 0.78, 1.36)

ARR* 1.7%

*Based on cumulative incidence

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Efficacy: Subgroup with Baseline LDL-C 100 mg/dL(Median Baseline LDL-C 118 mg/dL)


(N=2814)Placebo

(N=2815)Absolute

risk reduction (%)HR (95% CI)

MACE 324 (11.5) 420 (14.9) 3.4 0.76 (0.65, 0.87)

CHD death 69 (2.5) 96 (3.4) 1.0 0.72 (0.53, 0.98)

CV death 81 (2.9) 117 (4.2) 1.3 0.69 (0.52, 0.92)

All-cause death 114 (4.1) 161 (5.7) 1.7 0.71 (0.56, 0.90)

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Safety (1)

Treatment-emergent adverse events, n (%)

Alirocumab(N=9451)

Placebo(N=9443)

Any 7165 (75.8) 7282 (77.1)

Serious 2202 (23.3) 2350 (24.9)

Laboratory value Alirocumab Placebo

ALT >3 ULN, n/N (%) 212/9369 (2.3) 228/9341 (2.4)

Creatine kinase >10 ULN, n/N (%) 46/9369 (0.5) 48/9338 (0.5)

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Safety (2)

EventAlirocumab

(N=9451)Placebo

(N=9443)

Diabetes worsening or diabetic complications: ptsw/DM at baseline, n/N (%)

506/2688 (18.8) 583/2747 (21.2)

New onset diabetes; pts w/o DM at baseline, n/N (%) 648/6763 (9.6) 676/6696 (10.1)

General allergic reaction, n (%) 748 (7.9) 736 (7.8)

Hepatic disorder, n (%) 500 (5.3) 534 (5.7)

Local injection site reaction, n (%)* 360 (3.8) 203 (2.1)

Neurocognitive disorder, n (%) 143 (1.5) 167 (1.8)

Cataracts, n (%) 120 (1.3) 134 (1.4)

Hemorrhagic stroke, n (%) 9 (<0.1) 16 (0.2)

*HR vs. placebo 1.82 (95% CI 1.54, 2.17)

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Conclusions

Compared with placebo in patients with recent ACS, alirocumab 75 or 150 mg subcutaneous Q2W targeting LDL-C levels 25–50 mg/dL, and allowing levels as low as 15 mg/dL:

1. Reduced MACE, MI, and ischemic stroke

2. Was associated with a lower rate of all-cause death

3. Was safe and well-tolerated over the duration of the trial

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Clinical Perspective

• In this nearly 19,000-patient placebo-controlled trial, including many patients treated for ≥3 years, there was no safety signal with alirocumab other than injection site reactions

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Clinical Perspective

• In this nearly 19,000-patient placebo-controlled trial, including many patients treated for ≥3 years, there was no safety signal with alirocumab other than injection site reactions

• Among patients with ACS and baseline LDL-C 100 mg/dL, alirocumab reduced MACE by 24% (ARR 3.4%) and all-cause death by 29% (ARR 1.7%) compared with placebo

These are the patients who may benefit most from treatment

ARR, absolute risk reduction

Backup

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Blinded Alirocumab Dose Adjustments

All patients assigned to alirocumab 75 mg

Q2W

LDL-C measured at Month 1

Up-titration of alirocumab for LDL-C ≥50 mg/dL

LDL-C <50 mg/dL

Continue at 75 mg Q2W

LDL-C ≥50 mg/dL

Blinded increase to

150 mg Q2W at Month 2

visit

LDL-C <25 mg/dL on 2 consecutive measurements

Down-titration of alirocumab and/or safety monitoring for LDL-C <25 mg/dL

If alirocumab 75 mg Q2W

LDL-C 15 to <25 mg/dL on ≥1

measurement

If alirocumab 150 mg Q2W

Blinded dose decrease to 75 mg Q2W

at next study visit

Safety monitoring

by independent

physician

LDL-C <15 mg/dL on 2 consecutive measurements

Blinded permanent discontinuation of

alirocumab and substitution of placebo

at next study visit

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FOURIER ODYSSEY OUTCOMES

Population Stable ASCVD Recent ACS

Qualifying LDL-C, mg/dL ≥70 ≥70

Primary endpoint5-point MACE:

CV death, MI, CVA, UA, coronary revasc.

4-point MACE:CHD death, MI, CVA, UA

Follow up 26 months 34 months

Age (median, years) 63 58

ACS <1 year 20% 100%

High-intensity statin 69% 89%

No statin 0.2% 2.5%

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Outcomes relative risk reduction

FOURIER ODYSSEY OUTCOMES

Primary endpoint 15% 15%

MI 27% 14%

Stroke 21% 27%

Unstable angina 1% 39%

CV death +5% increase (NS) 12% (NS)

All cause death +4% increase (NS) 15% (p=0.026*)

*Nominal P-value

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Main Outcomes

Overall cohort


(N=9462)Placebo

(N=9462)ARR NNT HR (95% CI)

Log-rank P-value

MACE 903 (9.5) 1052 (11.1) 1.6% 64 0.85 (0.78, 0.93) 0.0003

All-cause death 334 (3.5) 392 (4.1) 0.6% 163 0.85 (0.73, 0.98) 0.026*

Patients with baseline LDL-C ≥100 mg/dL


(N=2814)Placebo

(N=2815)ARR NNT HR (95% CI)

MACE 324 (11.5) 420 (14.9) 3.4% 29 0.76 (0.65–0.87)

All-cause death 114 (4.1) 161 (5.7) 1.7% 60 0.71 (0.56–0.90)

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Time to First Occurrence of MACE (Primary Endpoint) Per CEC, According to Baseline LDL-C (ITT Population)

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HR 0.76 (0.65–0.87) HR 0.91 (0.81–1.02)

Baseline LDL-C <100 mg/dL Baseline LDL-C 100 mg/dL

MACE Benefit Largely Driven by Patients With Baseline LDL-C 100 mg/dL

Pinteraction=0.05

Primary endpoint: time to first occurrence of MACE (Kaplan-Meier cumulative incidence curve in ITT population)

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Landmark Analysis (Post Hoc)

All patientsPatients with 100 md/dL LDL-C at

baseline

Overall HR0-12

MonthsBeyond 12

monthsOverall HR

0-12Months

Beyond 12 months

Time to first MACE event

0.85(0.78–0.93)

0.94(0.83–1.08)

0.77(0.69–0.87)

0.76 (0.65–0.87)

0.81(0.66–1.01)

0.71(0.58–0.87)

Time to first all-cause

death

0.85 (0.73–0.98)

1.01(0.77–1.32)

0.79(0.66–0.94)

0.71(0.56–0.90)

0.79(0.51–1.22)

0.67(0.50–0.89)

alirocumab in patients with recent acute coronary syndrome ... · acc.18 3 •remains high despite...

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